The ability to synthesize sterol esters is fundamental to most eukaryotic cells. Sterol esterification is thought to participate in the maintenance of cell membrane sterols at levels optimal for normal cell function. In mammalian cells, cholesterol esterification is catalyzed by the enzyme acyl CoA:cholesterol acyltransferase (E.C. 2.3.1.26, ACAT).
ACAT activity has been implicated in a number of physiologic processes. In the small intestine, ACAT has been proposed to play a role in cholesterol absorption by maintaining a free cholesterol diffusion gradient across the enterocyte surface through the intracellular formation of cholesterol esters. Cholesterol ester formation by ACAT has also been hypothesized to be important for the assembly and secretion of apolipoprotein B-containing lipoproteins in the intestine and the liver. In the adrenal glands and other steroidogenic tissues, ACAT synthesizes cholesterol esters that accumulate in cytosolic droplets where they can serve as cholesterol substrate stores for steroidogenesis. In macrophages, ACAT generates intracellular cholesterol esters that are stored as cytosolic lipid droplets, a characteristic feature of macrophage foam cells in atherosclerotic lesions.
Recent evidence has suggested that more than one ACAT exists in mammals. A human ACAT cDNA was first identified from a macrophage cDNA library. The disruption of the mouse homolog of this ACAT gene (Acact) yielded viable, ACAT-deficient (Acact−/−) mice that were characterized by tissue-specific reductions in cholesterol esters. Cholesterol ester stores were markedly reduced in adrenal cortices and cultured peritoneal macrophages; however, substantial levels of ACAT activity were present in Acact(−/− livers, and intestinal cholesterol absorption was normal, indicating that another ACAT enzyme was active in these tissues. Studies examining the tissue distribution of Acact mRNA expression also supported the hypothesis that more than one ACAT exists, as did previous biochemical and ACAT inhibitor studies showing differences between liver and aorta/macrophage ACAT activities. The above results indicate that a second ACAT enzyme contributes to cholesterol esterification activity in the liver and small intestine.
As such, there is much interest in the identification, isolation and characterization of this putative second ACAT enzyme.